Vaccines provide excellent immunity against severe SARS-CoV-2 infection, the virus responsible for the COVID-19 pandemic. Studies have shown that vaccines can reduceTrusted Source hospitalization and death risk by over 99% and up to 71.6% against infection with the Omicron variant.

There are three main types of COVID-19 vaccines that are currently widely used:

mRNA vaccines: These use laboratory-made messenger RNA to teach the body’s immune cells to make a protein that triggers the body’s immune response.
Viral vector vaccines: These vaccines use a harmless virus called the ‘vector virus,’ which is modified to deliver instructions to the immune cells to trigger them to produce antibodies to fight the infection.
Inactivated virus vaccines: These contain a dead version of a virus that cannot replicate but can trigger the body’s immune system to create antibodies to protect against the live virus if it were to invade.
The two main viral vector vaccines in use are ChAdOx1, developed by Oxford University-AstraZeneca, and Ad26.COV2.S, developed by Johnson & Johnson (J&J). Both vaccines use adenovirusesTrusted Source as vector viruses to mount an immune response against SARS-CoV-2.

Despite their success, adenovirus-based vaccines have been linked to a small numberTrusted Source of people who have experienced thrombosis with thrombocytopenia (TTS), a potentially life threatening blood clotting disorder.

A recent study carried out by scientists at Arizona State University and the Mayo Clinic, published in the journal Science Advances, shed light on the possible mechanisms. The authors also detailed the interaction between the AstraZeneca vaccine and protein stored inside the blood’s platelets called platelet factor (PF4)Trusted Source. PF4 is released when platelets are activated.

The risk of blood-clotting complications
The blood-clotting disorder TTS is a very rare condition.

A recent review by the Global Advisory Committee on Vaccine Safety (GACVS)Trusted Source for the World Health Organization (WHO) reported that 1 in 250,000 adults in the United Kingdom and approximately 1 per 100,000 vaccinated adults in the European Union (EU) developed TTS.

According to one dataset, approximately 63.8% of the world’s population has had 1 dose of a COVID-19 vaccine, amounting to over 11.04 billion doses globally. Studies and real-world data have shown that the risk of death with or due to COVID-19 is 93.4% lower in vaccinated people (3 doses).

Despite the low incidence of TTS, mass vaccination has resulted in some people developing the condition. Scientists do not understand the exact mechanism behind TTS.

However, they think that vaccination with an adenovirus causes platelet factor 4 (PF4)Trusted Source, a protein in the blood, to bind to the adenovirus, forming a complex. Platelets are the tiny blood cells that help the body form clots to stop bleeding. Some people form antibodiesTrusted Source against this antigen-PF4 complex, which causes the platelets to aggregate, leading to an increased risk of blood clots.

Computer models and laboratory tests
To investigate blood clots associated with the Oxford-AstraZeneca COVID-19 vaccine, researchers used state-of-the-art computer modeling to understand how the adenovirus-based jab interacted with the proteins of the human body.

The team began by defining the structure of the AstraZeneca viral vector before using Atomic Resolution Brownian Dynamics (ARBD) computational modeling to demonstrate the electrostatic interaction between the vaccine particle and PF4.

The team found PF4 formed stable complexes with the adenoviruses. They discovered that the negative charge of the vaccine particle attracted the positive charge of the PF4 protein.

As a possible solution to combat this, the scientists added heparin, a drug used to stop blood clotting, to the simulations. They saw that it prevented PF4 from sticking to the vaccine particle.

The researchers then carried out cell-based experiments to confirm the results from the ARBD modeling.

When asked if the same clotting mechanism could be responsible for the complications associated with the J&J adenovirus-based vaccine, manuscript first author Dr. Alexander Baker replied:

“I think it’s a bit early to say this is the main/only driver. That being said, yes, we did show Adenovirus type 26 capsid (J&J) can also bind to PF4 with a similar affinity.”

What this means for the future
Study co-lead, Dr. Abhishek Singharoy, assistant professor in the School of Molecular Sciences at Arizona State University, said, “It’s really critical to fully investigate the vector-host interactions of the vaccine at a mechanistic level…[T]his will assist in understanding both how the vaccine generates immunity, and how it may lead to any rare adverse events, such as [vaccine-induced immune thrombotic thrombocytopenia] VITT.”

However, some important questions remain:

Why does TTS occur in such a small number of vaccinated people?
Do these findings mean that scientists can reengineer the vaccine to prevent TTS?
Can scientists reduce the negative charge of the vaccine particle?
Clinically, can we predict which people are at higher risk from TTS, and can we develop alternative modified vaccines to prevent clots for these high risk individuals?
Despite these questions, Dr. Raghav Palankar, a researcher at the Institute of Immunology and Transfusion Medicine in Germany, has called the research “Quite a game-changing fundamental discovery with significant translational implications.”

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